p40 protein acts as an oncogene

Abstract

We have discovered p40, the shortest variant of a new human p53 homologue (p40/p51/p63/p73H). We have also found that it plays a role in cancer. Low level amplification of the p40 locus accompanied by RNA and protein overexpression was observed in primary lung cancers, and head and neck cancer cell lines. P40 protein overexpression in primary lung tumors was limited to squamous cell carcinoma, tumors known to harbor a high frequency of p53 mutations. Overexpression of p40 in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. We searched for p40 binding proteins using the yeast two-hybrid system. P53 was the most common binding target of the 1.6x106 clones screened from a mouse embryonic library. Moreover, coexpression of p40 and p53 led to a decrease in p53 transcriptional activity. Our results support the notion that p40 plays an oncogenic role in human cancer.

What is claimed is:  
     
       1. A cDNA molecule which encodes a p40 protein having an amino acid sequence which is at least 99% identical to SEQ ID NO:2, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1. 
     
     
       2. The cDNA molecule of  claim 1  which comprises a nucleotide sequence shown in SEQ ID NO:1. 
     
     
       3. A cDNA molecule which is at least 99% identical to the nucleotide sequence shown in SEQ ID NO:1, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1. 
     
     
       4. A nucleic acid construct comprising: 
       a promoter; and  
       a polynucleotide segment encoding a p40 protein as shown in SEQ ID NO:2, wherein the polynucleotide segment is located downstream from the promoter, wherein transcription of the polynucleotide segment initiates at the promoter, wherein the promoter is not the endogenous p40 promoter.  
     
     
       5. A host cell comprising a nucleic acid construct which comprises: 
       a promoter and:  
       a polynucleotide segment encoding a p40 protein having an amino acid sequence as shown in SEQ ID NO:2, wherein the promoter is not the endogenous p40 promoter.  
     
     
       6. A cDNA molecule which encodes a p40 protein consisting of an amino acid sequence which is at least 99% identical to SEQ ID NO:2, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1. 
     
     
       7. The cDNA molecule of  claim 6  which comprises a nucleotide sequence shown in SEQ ID NO:1. 
     
     
       8. A cDNA molecule which encodes a p40 protein which has an apparent molecular weight of 40 kDa, said protein having an amino acid sequence which is at least 99% identical to SEQ ID NO:2, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1. 
     
     
       9. The cDNA molecule of  claim 8  which comprises a nucleotide sequence shown in SEQ ID NO:1. 
     
     
       10. A nucleic acid construct comprising: 
       a promoter; and  
       a polynucleotide segment encoding a p40 protein as shown in SEQ ID NO:2, wherein the p40 protein has an apparent molecular weight of 40 kDa, wherein the polynucleotide segment is located downstream from the promoter, wherein transcription of the polynucleotide segment initiates at the promoter, wherein the promoter is not the endogenous p40 promoter.  
     
     
       11. A nucleic acid construct comprising: 
       a promoter; and  
       a polynucleotide segment encoding a p40 protein which consists of the sequence shown in SEQ ID NO:2, wherein the polynucleotide segment is located downstream from the promoter, wherein transcription of the polynucleotide segment initiates at the promoter, wherein the promoter is not the endogenous p40 promoter.  
     
     
       12. A host cell comprising a nucleic acid construct which comprises: 
       a promoter and:  
       a polynucleotide segment encoding a p40 protein having an amino acid sequence as shown in SEQ ID NO:2, wherein the p40 protein has an apparent molecular weight of 40 kDa, and wherein the promoter is not the endogenous p40 promoter.  
     
     
       13. A host cell comprising a nucleic acid construct which comprises: 
       a promoter and:  
       a polynucleotide segment encoding a p40 protein having an amino acid sequence as shown in SEQ ID NO:2, wherein the p40 protein consists of the amino acid sequence shown in SEQ ID NO:2, and wherein the promoter is not the endogenous p40 promoter.  
     
     
       14. A cDNA molecule which consists of a molecule which is at least 99% identical to the nucleotide sequence shown in SEQ ID NO:1, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1. 
     
     
       15. A cDNA molecule which is at least 99% identical across its entire length to the nucleotide sequence shown in SEQ ID NO:1, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.